A pharmacological protocol for the management of medication-related osteonecrosis of the jaws: A randomized study

ISRCTN ISRCTN18375975
DOI https://doi.org/10.1186/ISRCTN18375975
Submission date
29/06/2023
Registration date
06/07/2023
Last edited
06/08/2024
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Musculoskeletal Diseases
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Background and study aims
Medication-related osteonecrosis of the jaws (MRONJ) is a challenging situation in clinics. Previous studies showed that pentoxifylline (PTX) combined with tocopherol was beneficial in patients with osteoradionecrosis, due to its antioxidant and antifibrotic properties. This study aims to evaluate the effect of PTX and tocopherol in patients with MRONJ.

Who can participate?
Female Stage I MRONJ patients with osteoporosis who had developed MRONJ after tooth extractions

What does the study involve?
The test group receives the pharmacological protocol with PTX and tocopherol (2 months pre-operatively and 6 months post-operatively). The control group has sequestrectomy operations (surgical removal of necrotic bone) without any pharmacological preparation. The main outcomes are clinical healing of the mucosa after 1 month and clinical and radiographic healing of the bone lesion at 6 months.

What are the possible benefits and risks of participating?
It is expected that in osteoporosis patients with Stage I MRONJ, the proposed pharmacological treatment with PTX and tocopherol will improve mucosal and bone healing rates and minimize relapses and complications, as compared to the control group.

The drugs used in the study are safe; pentoxifylline (PTX) is a methylxanthine derivate that was originally approved by the Food and Drug Administration (FDA) to treat peripheral artery diseases and has been used to treat complications related to fibrosis for over 20 years. PTX increases vasodilation and erythrocyte flexibility and reduces blood viscosity, which leads to an improvement in peripheral blood flow and tissue oxygenation. Tocopherols are organic chemical compounds consisting of various methylated phenols with beneficial effects. Tocopherols decrease tissue fibrosis, reduce inflammation, and have antioxidant effects that protect cell membranes from lipid peroxidation by reducing the free radical damage generated during oxidative stress. PTX in combination with tocopherol has a synergistic effect and is used for the management of osteoradionecrosis, with beneficial antioxidant and antifibrotic properties. The main risk for participants receiving the pharmacological treatment is that it is ineffective, and the chance of developing relapses or worsening the disease after the intervention remains high. No other risks other than those commonly associated with surgical intervention (e.g. post-operative bleeding, pain, swelling, infection) are foreseen.

Where is the study run from?
Department of Oral Surgery and Maxillofacial Surgery, Francesco Miulli Regional Hospital, University of Bari (Bari, Italy), and Oral Med Care srl, Regional Dental Medical Centre of Oral Surgery and Maxillofacial Surgery (Bitonto, Italy).

When is the study starting and how long is it expected to run for?
June 2013 to January 2023

Who is funding the study?
Francesco Miulli Regional Hospital (Generale Regionale Francesco Miulli) (Italy)

Who is the main contact?
Dr. Gianluca Colapinto, colapinto.gianluca@virgilio.it
Prof. Massimo Del Fabbro, massimo.delfabbro@unimi.it

Contact information

Dr Gianluca Colapinto
Principal Investigator

Via Giuseppe Capaldi n 9
Bitonto
70032
Italy

Phone +39 (0)3887913143
Email oralmedcaresrl@gmail.com
Prof Massimo Del Fabbro
Scientific

Department of Biomedical, Surgical and Dental Sciences, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano
Via della Commenda 10
Milano
20122
Italy

Phone +39(0)3496451220
Email massimo.delfabbro@unimi.it

Study information

Study designSingle-centre interventional randomized controlled trial
Primary study designOther
Secondary study design
Study setting(s)Hospital
Study typeTreatment
Participant information sheet Not available in web format, please use contact details to request a participant information sheet
Scientific titleEffectiveness of a pharmacological protocol with pentoxifylline and tocopherol for the management of medication-related osteonecrosis of the jaws (MRONJ): A randomized study on 202 osteoporosis patients.
Study objectivesThe aim is to verify that pharmacological treatment of preparation with pentoxifylline and tocopherol in patients affected by MRONJ and candidates for surgery, improves mucosal and bone healing rates compared to patients affected by MRONJ and candidates for surgery not undergoing pharmacological preparation.
Ethics approval(s)

Approved 13/02/2014, Institutional Review Board of the Francesco Miulli Regional Hospital (Strada Prov. 127 Acquaviva – Santeramo Km. 4, 70021, 70021 Acquaviva delle Fonti BA, ACQUAVIVA delle FONTI, 70021, Italy; +39 (0)803054111; protocollo.miulli@legalmail.it), ref: 203077-13/02/2014

Health condition(s) or problem(s) studiedMedication-related osteonecrosis of the jaws (MRONJ) in osteoporosis patients
InterventionAll patients are randomly divided into two groups, a test group and a control group, in a double-blind manner. The test group will receive the pharmacological preparation with pentoxifylline (600 mg x 2/day) and tocopherol (800 IU x 1/day) from 2 months before to 6 months after the surgical procedure, while the control group will directly receive the surgical procedure. The results will be evaluated and it will be verified whether the pharmacological preparation improves the results.
Intervention typeDrug
Pharmaceutical study type(s)Not Applicable
PhaseNot Applicable
Drug / device / biological / vaccine name(s)Pentoxifylline, tocopherol
Primary outcome measure1. Mucosal healing measured clinically by visual inspection at 1 week, 2 weeks, 1 month, 2, 6, and 12 months after the intervention
2. Bone healing measured clinically and radiographically through cone beam computed tomography (CBCT) 6 and 12 months after the intervention
Secondary outcome measuresThe following secondary outcome measures will be observed yearly from 1 year up to 8 years:
1. Stability of mucosal and bone healing measured using clinical observation of the absence of inflammatory signs and maintenance of closure without bone exposure for mucosal healing, and radiographic assessment of healthy bone with normal structure, using cone beam computed tomography (CBCT)
2. Incidences of complications, such as abscess, mucosal fistula, and phlegmon, measured throughout all the study using clinical inspection and patient's reported complaints
3. Relapses occurring when mucosal healing has occurred, but bone healing does not occur, which can lead to two scenarios:
3.1. The mucosa reopens with exposure to underlying necrotic bone
3.2. The mucosa remains closed, but a small fistula is created where it is possible to probe the underlying unhealed necrotic bone measured using clinical and radiographic evaluation
Overall study start date01/06/2013
Completion date31/01/2023

Eligibility

Participant type(s)Patient
Age groupAdult
SexFemale
Target number of participants202
Total final enrolment202
Key inclusion criteriaPatients with osteoporosis and MRONJ stage I
Key exclusion criteria1. Cancer patients with metastatic bone disease
2. Other stages of MRONJ
Date of first enrolment01/08/2013
Date of final enrolment01/11/2017

Locations

Countries of recruitment

  • Italy

Study participating centres

Department of Oral Surgery and Maxillofacial Surgery, of the Francesco Miulli Regional Hospital, University of Bari
Strada Prov. 127 Acquaviva – Santeramo Km. 4
Acquaviva delle Fonti
70021
Italy
Oral Med Care srl, Regional Dental Medical Centre of Oral Surgery and Maxillo-Facial Surgery
Via Giuseppe Capaldi n 9
Bitonto
70032
Italy

Sponsor information

Ospedale Generale Regionale Francesco Miulli
Hospital/treatment centre

Strada Prov. 127 Acquaviva – Santeramo Km. 4
Acquaviva delle Fonti
70021
Italy

Phone +39 (0)803054111
Email protocollo.miulli@legalmail.it
Website http://www.miulli.it/
ROR logo "ROR" https://ror.org/03djvm380

Funders

Funder type

Hospital/treatment centre

Ospedale Generale Regionale Francesco Miulli

No information available

Results and Publications

Intention to publish date15/07/2023
Individual participant data (IPD) Intention to shareYes
IPD sharing plan summaryAvailable on request
Publication and dissemination planPlanned publication in a high-impact peer-reviewed journal
IPD sharing planData analysed during the current study will be available upon request from Prof Massimo Del Fabbro (massimo.delfabbro@unimi.it)

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Results article 13/07/2023 06/08/2024 Yes No

Editorial Notes

06/08/2024: Publication reference added.
06/07/2023: Trial's existence confirmed by the Maxillofacial Surgery Department, Francesco Miulli Regional Hospital (Generale Regionale Francesco Miulli) (Italy).